The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)-dependent PGE2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE2→MMP-9 pathway in murine macrophages. IL-6 co-induced Cox-2 and microsomal prostaglandin E synthase-1 (mPGES-1), and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), leading to increased levels of PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6–mediated induction of MMP-9. In the canonical model of IL-6-induced signaling, JAK activation triggers STAT and MAPKerk1/2-signaling pathways. Therefore, the ability of structural diverse JAK inhibitors to block IL-6-induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6 induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPKerk1/2, and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6 induced phosphorylation of MAPKerk1/2 and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6-induced MMP-9 expression is dependent on the activation of MAPKerk1/2 and restrained by a JAK-dependent gene product. Utilizing pharmacologic and genetic approaches, JAK-dependent induction of IL-10 was identified as a potent feedback mechanism controlling IL-6 induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2-dependent and -independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.

MMP-9 contributes to the pathogenesis of chronic inflammatory diseases and cancer. Thus, identifying targetable components of signaling pathways that regulate MMP-9 expression may have broad therapeutic implications. Our previous studies revealed a nexus between metalloproteinases and prostanoids whereby MMP-1 and MMP-3, commonly found in inflammatory and neoplastic foci, stimulate macrophage MMP-9 expression via the release of TNF-α and subsequent induction of cyclooxygenase-2 (Cox-2), and PGE2 engagement of EP4 receptor. In the present studies, we determined whether MMP-induced Cox-2 expression was coupled to the expression of PGE synthase family members. We found that MMP-1 and MMP-3-dependent release of TNF-α induced rapid and transient expression of Egr-1 in macrophages followed by sustained elevation in mPGES-1 expression. Metalloproteinase-induced PGE2 levels and MMP-9 expression were markedly attenuated in macrophages in which mPGES-1 was silenced, thereby identifying mPGES-1 as a therapeutic target in the regulation of MMP-9 expression. Finally, the induction of mPGES-1 was regulated, in part, through a positive feedback loop dependent on PGE2 binding to EP4. Thus, in addition to inhibiting macrophage MMP-9 expression, EP4 antagonists emerge as potential therapy to reduce mPGES-1 expression and PGE2 levels in inflammatory and neoplastic settings.

Background As the number of coronavirus disease 2019 (COVID-19) cases increases globally, more cases of a rare COVID-19–associated disease process are being identified in the pediatric population. This syndrome is referred to as multisystem inflammatory syndrome in children (MIS-C). Clinical manifestations of the syndrome vary and include one or a combination of the following: vasodilatory shock, cardiogenic shock, Kawasaki-like disease, cytokine storming, coronary artery dilatation, and aneurysms. Case Report This case report describes the presentation, findings, workup, and treatment for a 9-year-old boy diagnosed with MIS-C. Why Should an Emergency Physician Be Aware of This? It is important to recognize MIS-C, as it shares many of the same features as other disease processes, for example, Kawasaki disease and toxic shock syndrome, but has different complications if left untreated.

The mPGES-1 PCR blots in Fig. 8C were inadvertently duplicated from the Egr-1 blots due to an error in figure preparation. The corrected version of Fig. 8 is shown below. The figure legend was correct as published and is shown below for reference.

Elevated plasma IL‐6 levels are associated with an increased risk for coronary heart disease; however, causality remains undefined. We previously reported that COX‐2‐dependent PGE2 synthesis and binding to EP4 stimulates macrophage MMP‐9 expression, which has been implicated in the pathogenesis of vascular diseases. In the present studies, we determined whether IL‐6 regulates the COX‐2→PGE2→EP4 receptor axis in macrophages. Results demonstrate that IL‐6 inhibited macrophage expression of 15‐PDGH, and stimulated expression of COX‐2 and mPGES‐1, resulting in an increase in PGE2 levels. Likewise, IL‐6‐induced MMP‐9 expression in macrophages. Whereas, the COX‐2 inhibitor celecoxib completely blocked IL‐6 induced PGE2 synthesis, MMP‐9 expression was partially attenuated. These data reveal COX‐2‐ dependent and independent mechanisms through which IL‐6 stimulates MMP‐9 expression. Engagement of the IL‐6 receptor triggers activation of the JAK/STAT and MAPK pathways leading to the expression of target genes. Pre‐incubation of macrophages with the JAK inhibitor tofacitinib blocked expression of several IL‐6‐induced genes, but paradoxically stimulated MMP‐9 expression. In contrast, MMP‐9 expression was completely blocked by the MEK inhibitor U0126. Thus, inhibition of MAPK emerges as a major strategy to block IL‐6‐induced MMP‐9 expression in macrophages. These studies were supported by HL093331.